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Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

About this Publication
Title
Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.
Pubmed ID
27579533 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Oncotarget. 2016 Oct 11; Volume 7 (Issue 41): Pages 66328-66343
Authors
Zhang M, Wang Z, Obazee O, Jia J, Childs EJ, Hoskins J, Figlioli G, Mocci E, Collins I, Chung CC, Hautman C, Arslan AA, Beane-Freeman L, Bracci PM, Buring J, Duell EJ, Gallinger S, Giles GG, Goodman GE, Goodman PJ, ...show more Kamineni A, Kolonel LN, Kulke MH, Malats N, Olson SH, Sesso HD, Visvanathan K, White E, Zheng W, Abnet CC, Albanes D, Andreotti G, Brais L, Bueno-de-Mesquita HB, Basso D, Berndt SI, Boutron-Ruault MC, Bijlsma MF, Brenner H, Burdette L, Campa D, Caporaso NE, Capurso G, Cavestro GM, Cotterchio M, Costello E, Elena J, Boggi U, Gaziano JM, Gazouli M, Giovannucci EL, Goggins M, Gross M, Haiman CA, Hassan M, Helzlsouer KJ, Hu N, Hunter DJ, Iskierka-Jazdzewska E, Jenab M, Kaaks R, Key TJ, Khaw KT, Klein EA, Kogevinas M, Krogh V, Kupcinskas J, Kurtz RC, Landi MT, Landi S, Le Marchand L, Mambrini A, Mannisto S, Milne RL, Neale RE, Oberg AL, Panico S, Patel AV, Peeters PH, Peters U, Pezzilli R, Porta M, Purdue M, Quiros JR, Riboli E, Rothman N, Scarpa A, Scelo G, Shu XO, Silverman DT, Soucek P, Strobel O, Sund M, Małecka-Panas E, Taylor PR, Tavano F, Travis RC, Thornquist M, Tjønneland A, Tobias GS, Trichopoulos D, Vashist Y, Vodicka P, Wactawski-Wende J, Wentzensen N, Yu H, Yu K, Zeleniuch-Jacquotte A, Kooperberg C, Risch HA, Jacobs EJ, Li D, Fuchs C, Hoover R, Hartge P, Chanock SJ, Petersen GM, Stolzenberg-Solomon RS, Wolpin BM, Kraft P, Klein AP, Canzian F, Amundadottir LT
Affiliations
  • Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA.
  • Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
  • Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
  • Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
...show more
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • Group Health Research Institute, Seattle, Washington, USA,.
  • Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain.
  • Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
  • Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
  • Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
  • Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
  • Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy,.
  • Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, F-94805, Villejuif, France.
  • Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Biology, University of Pisa, Pisa, Italy.
  • Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy.
  • Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada.
  • National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom.
  • Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy.
  • Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
  • Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA.
  • Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
  • Preventive Medicine, University of Southern California, Los Angeles, California, USA.
  • Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
  • Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Department of Hematology, Medical University of Łodz, Łodz, Poland.
  • International Agency for Research on Cancer (IARC), Lyon, France.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
  • School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
  • Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  • Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
  • Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
  • Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
  • Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy.
  • National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland.
  • Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  • Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
  • Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy.
  • Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
  • Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
  • Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain.
  • Public Health and Participation Directorate, Asturias, Spain.
  • Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
  • ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
  • Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
  • Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
  • Department of Surgical and Peroperative Sciences, Umeå University, Umeå, Sweden.
  • Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland.
  • Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
  • Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
  • Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, Hamburg, Germany.
  • Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
  • Department of Social and Preventive Medicine, University at Buffalo, Buffalo, New York, USA.
  • Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA,.
  • Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.
  • Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
Abstract

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

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